Transdermal fertility control system and process

ABSTRACT

Transdermal fertility-controlling absorption polymer matrix dosage units have been developed which comprise a backing layer, an adjoining layer of a solid polymer matrix in which minimum effective daily doses of an estrogen and a progestin are microdispersed and released for transdermal absorption. Presently preferred is use of the natural estrogen, 17-beta-estradiol, and of the progestin, levonorgestrel. The units have a biologically acceptable adhesive polymer layer. The polymer matrix as well as the adhesive layer can have dispersed one or more skin permeation enhancers. Dosage units are provided which transdermally deliver at least minimum daily doses of the estrogen and progestin for multiple days, such as for one week. The invention also provides a process of fertility control using the novel polymer matrix dosage units for the first three weeks of consecutive menstrual cycles of the subject desiring fertility control.

This invention was made with Government support under the NationalInstitute of Child Health and Human Development, Grant No.N01-HD-5-2912, and the Government has a right to a license to theinvention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is continuation-in-part of both U.S. application Ser.No. 06/704,194, filed Feb. 25, 1985, by Yie W. Chien and Chia-Shun Leeand U.S. application Ser. No. 06/770,968, filed Aug. 30, 1985, by Yie W.Chien and Chia-Shun Lee.

This invention relates to a novel transdermal fertility control systemand a process for controlling fertility. The system involves transdermalabsorption dosage units adapted for adhesion to the female subjectdesiring fertility control or prevention of an unwanted pregnancy.Additionally, the invention relates to a method of controlling fertilityby utilizrng a transdermal system of applying a series of transdermalpolymer matrix dosage units having microdispersed in the matrix layereffective dosage amounts of an estrogen, preferably 17-beta-estradioland a progestin, preferably levonorgestrel.

BACKGROUND ART

Fertility has been controlled by use of a number of orally administeredhormone products. The products are ordinarily a combination of anestrogen and a progestin. A synthetic estrogen is ordinarily used as theestrogen component since the natural estrogen, 17-beta-estradiol, isalmost completely destroyed, usually over 90 percent, when taken orally.It is destroyed to a degree in the digestive tract be tore it isabsorbed but primarily the destructive metabolism of 17-beta-estradioloccurs during the "first pass" hepatic metabolism. Since such a largeamount is destroyed, in order to provide an effective dosage orally, alarge excess must be administered with uncertain effectiveness and alarge amount of unwanted metabolic products. Therefore, a syntheticestrogen such as ethinyl estradiol normally is administered with lessthan desired results.

The progestin component generally inhibits, as intended, ovulation.Also, in the case of administered progestin, a substantial amount ofmetabolic breakdown occurs causing undesired metabolic products withundesired effects.

Therefore, in the oral administration of what is commonly referred to as"the pill" or other orally administered products, considerablyoverdosing is necessary to obtain a high degree of assurance that thedesired fertility control will be obtained.

A number of major side effects have reportedly been associated with theadministration of oral fertility control preparations, likethrombophlebitis and thrombosis, pulmonary embolism, coronarythrombosis, myocardial infarction, cerebral thrombosis, cerebralhemorrhage and hypertension. These side effects have been attributed tothe estrogen component in the oral preparations. Use of theprogestinonly preparations (mini-pill) has been found to eliminate theside effects of estrogen. However, the fertility control is less thanthat of the combined preparations and the menstrual cycle also becomesmore irregular. It has been reported that less incidence of irregularbleeding is observed if the progestin is administered at a more constantrate of delivery. Besides the side effects, the oral fertility controlpreparations also have the disadvantage of fertility control efficacydepending highly on the degree of patient compliance. The risk ofpregnancy is known to increase with each pill missed.

An ideal and patient-acceptable fertility control system should providethe following advantages: minimized side effect, increased ease ofadministration, rapid termination of treatment, if needed, and improvedpatient compliance. In recent years, considerable attention has alreadybeen directed to the development of implantable, intrauterine,intracervical or intravaginal fertility control delivery systems toprovide a prolonged and controlled administration of steroidal hormonesto the body for achieving fertility control; however, none of thedelivery systems developed so far can be considered as ideal and sideeffect-free.

Other fertility control means have been used, such as topical creams andintravaginal devices, which deliver combinations of one or moreprogestins and one or more estrogens, including the naturally-occurringestrogen, 17-beta-estradiol. However, the undesirable aspects of suchfertility control systems are evident.

It is, therefore, highly desired that transdermal systems be providedwhich permit (1) use of the natural estrogen, 17-beta-estradiol, (2) useof a minimum number of dosage units for each menstrual cycle, such asuse of three successive weekly dosage units, (3) would adhere to theskin of the subject and provide sufficiently high levels of estrogen andprogestin hormones to provide high assurance of fertility controlwithout a high amount of undesired metabolic or chemical degradativeproducts. Development of a ratecontrol transdermal drug delivery system,which is capable of minimizing any individual variability and regionaldifferences in skin permeability, is a necessity to attain a predictableblood level of a drug. The transdermal ratecontrol drug administrationis known to offer several potential advantages for systemic medication:(i) avoidance of the risk and inconvenience of intravenous therapy andof the variability in absorption and metabolism associated with oraltherapy; (ii) continuity of drug administration, permitting the use of apharmacologically-active agent with short biological half-life; (iii)efficacy can be achieved with lower total daily dosage of drug, becauseof reduced hepatic first-pass metabolism and continuous drug input; (iv)less chance of over- or under-dosing, as a result of prolonged,programmed delivery of drug at required therapeutic rate; (v) provisionof a simplified medication regimen; and (vi) ability to rapidlyterminate the drug infusion, if needed, by removal of the drug deliverysystem from skin surface. Therefore, a transdermal contraceptivedelivery system, which is capable of providing dual-delivery of anestrogen and a progestin at controlled rates for a specific durationwould be an ideal system for achieving fertility regulation in women.

SUMMARY OF INVENTION

Provided by this invention is a transdermal fertility control absorptionsystem which permits fertility control by using sequentially threetransdermal adhesive dosage units which can easily be applied to aselected skin area.

The first patch ordinarily is applied on the fifth day of a menstrualcycle. The dosage unit is replaced by the second unit after 7 days andthe second is replaced by a third at the end of another 7 days. Then, atthe beginning of the next menstrual cycle, another sequential course of3 fertility control patches is again used, which course is repeatedagain and again as long as desired.

The transdermal fertility control dosage units of this inventioncomprise:

(a) a backing layer which is substantially impervious to the estrogenand progestin hormones to be delivered transdermally;

(b) a polymer matrix disc layer which is in contact with said backinglayer and which has micro-dispersed therein an amount of estrogen andprogestin hormone capable of transdermal absorption, said disc layerproviding a dosage amount of the hormones to be delivered transdermally;and

(c) an adhesive means which adheres the dosage unit in intimate contactwith the skin of the subject being treated to permit the hormones to beabsorbed transdermally.

The hormones microdispersed therein comprise an amount of17-beta-estradiol or other desired estrogen effective in providing therole of estrogen in fertility control and an amount of levonorgestrel orother desired progestin which will provide the role of progestin in thedesired fertility control system. Desirably, the dosage units willprovide the desired rate of transdermal absorption of the estrogen andprogestin components for a several day period, preferably for one week.Use of week-long transdermal dosage units minimize the possibility ofmissed administration of a dosage during the required fertility controlperiod of days.

The backing layer is made from materials that are substantiallyimpermeable with regard to the hormones of the transdermal dosage unit.It can be made of polymers such as polyethylene, polypropylene,polyurethane, polyvinylchloride, polyesters such as poly(ethylenephthalate), and foils such as laminates of polymer films with metallicfoils such as aluminum foil.

The polymer matrix disc layer is suitably fabricated from biologicallyacceptable lipophilic polymers. The polymer matrix disc layer which hasthe hormones distributed therein can suitably be made of a medical-gradesilicone polymer such as a polydimethylsiloxane polymer. The siliconepolymer can also be a block or graft or other type copolymer. Thehormones are suitably dispersed in the silicone polymer, to whichmixture a curing agent is suitably added. The polymer-hormone mixture isthen formed into a layer of an appropriate thickness and suitablesurface area and is cured, if desired. The matrix layer is adhered tothe backing layer. Other suitable polymers which can be used in theformulation of the polymer matrix disc layer are elastomers orthermoplastics. Care must be taken that the polymer selected iscompatible with the pharmaceutical, permits its release for transdermalabsorption and is free or sufficiently free from any biologicallyunacceptable components.

The estrogen hormone is preferably the naturally occurring estrogen:17-beta-estradiol. Other estrogenic steroid hormones can be used inpartial or complete replacement of 17-beta-estradiol. For example, anester which is biologically compatible and can be absorbed effectivelytransdermally. Also, it is ordinarily desired that such esters arebioconvertible by components of the skin or other portions o i the body,such as hydrolytical enzymes (e.g., esterase), to 17-beta-estradiol orother desired estrogenic steroid. If the derivative is an ester, thederivative can be a mono- or di-ester if the estrogenic steroid has twoesterifiable groups. In the case of estradiol, it has hydroxy groups atthe 3- and 17- positions and, therefore, the 3-mono and 17-mono as wellas the 3,17 di-esters can be made by generally known esterificationmethods. Some ester derivatives will be absorbed more readily than thebasic 17-beta-estradiol or other estrogenic steroid, which is the basiccompound. In selection of ester derivatives, it is ordinarily preferredthat the main estrogen hormone used be absorbed at a rate to provide adesirable amount of the estrogen hormone component on a daily basis in asystem which simultaneously effects transdermal absorption of theprogestin hormone in an effective daily dosage amount over a several dayperiod, preferably one week.

Valerate mono- and di-esters of estradiol are presently considered to bedesirable esters. In formulating the polymer disc layer, it is desirableat times to utilize two or more estrogens, such as the combination of anestradiol ester, like estradiol valerate, with an amount of17-beta-estradiol.

A presently preferred progestin is levonorgestrol. About 20 cg/day ofprogestin based on levonorgestrol and about 25 mcg/day of estrogen basedon 17-beta-estradiol are presently believed desired daily doses forhumans.

Finally, the adhesive means of the dosage unit is assembled with theother layer elements to form the dosage units. The adhesive meansselected can vary depending on many factors including economic factorssuch as the type of manufacturing equipment most readily available, therapidity of absorption desired or other factors. For example, theadhesive layer can be applied directly to the polymer matrix disc layer.A skin permeation enhancer compound can be mixed thoroughly with theadhesive polymer which is suitable for adhesion to the skin locus towhich the transdermal matrix dosage unit will be applied. The adhesivepolymer-skin permeation enhancer layer can be applied to the polymermatrix disc layer by spraying or by solvent casting or laminating. Theconcentration of skin permeation enhancer compound, if employed, can bereduced in the portion of the adhesive layer means, especially if lessthan desired adhesion is realized in the adhesive layer, by applying thesurface portion of the adhesive layer, separately, wherein the adhesivecomposition has a lower concentration of skin permeation enhancercompound. The adhesive layer is desirably thin in the micron-rangethickness, suitable 10-200 microns in thickness, desirably about 20 to180 microns, and preferably about 30 to 150 microns in thickness. Aneffective amount of a skin permeation enhancer compound can also beincorporated into the hormone-containing disc layer. Also, if desired,the adhesive means can be in the form of a ring adhered to the backinglayer which extends beyond the circumference of the disc layer. Whensuch a concentric ring adhesive means is employed, the exposed surfaceof the hormone-containing disc layer is held in intimate contact wit theskin of the subject treated.

The absorption rate of the transdermal hormone absorption dosage unitsof the invention can be increased, such as by having an Enhancing Factorof at least 1.2, preferably at least 1.3, and more preferably at leastabout 1.5. Enhancing Factor is defined as the ratio of normalizedpermeation rate [in mcg/cm² /hr] of a dosage unit of this invention withskin permeation enhancer/the normalized permeation rate of acorresponding dosage unit without enhancer.

The invention also is a process for administering said hormonestransdermally by forming hormone-containing polymer matrix disc dosageunit having a polymer matrix disc layer which has the hormone dosagesdispersed therein, to which matrix disc is adhered a backing layer, saiddosage unit having assembled therewith an adhesive means to hold thedosage unit in intimate contact with the skin of the subject treated sothat the hormones are absorbed transdermally, and by applying saiddosage unit by way of said adhesive means to the skin of the subject tobe treated, whereby said hormones are transdermally administered to saidsubject to achieve fertility control.

DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The backing layer can be made of any suitable material which isimpermeable to the hormones of the polymer matrix layer. The backinglayer serves as a protective cover for the matrix layer and providesalso a support function. The backing can be formed so that it isessentially the same size layer as the hormone-containing matrix disclayer or it can be of larger dimension so that it can extend beyond theside f the matrix disc layer or overlay the side or sides of thehormone-containing disc layer and then can extend outwardly in a mannerthat the surface of the extension of the backing layer can be the basefor an adhesive means. For long-term applications, e.g., for seven days,it might be desirable to use microporous and/or breathable backinglaminates, so hydration or maceration of the skin can be minimized. Theadhesive means holds the dosage unit in intimate contact with the skinof the subject treated. Examples of materials suitable for making thebacking layer are films of high and low density polyethylene,polypropylene, polyurethane, polyvinylchloride, polyesters such aspoly(ethylene phthalate), metal foils, metal foil laminates of suchsuitable polymer films, and the like . Preferably, the materials usedfor the backing layer are laminates of such polymer films with a metalfoil such as aluminum foil. In such laminates, a polymer film of thelaminate will usually be in contact with the polymer matrix layer. Thebacking layer aan be any appropriate thickness which will provide thedesired protective and support functions. A suitable thickness will befrom about 10 to about 200 microns. Desirably, the thickness will befrom about 20 to about 150 microns, and preferably be from about 30 toabout 100 microns.

The polymer matrix layer can be made from silicone elastomers of thegeneral polydimethylsiloxane structure, such as silicone polymers of thefollowing general formula: ##STR1## wherein R is alkyl or alkoxycontaininl-7 carbon atoms, vinyl or phenyl and wherein n is about 100 toabout 5000.

The silicone polymers selected preferably are cross-linkable at moderatetemperatures, such as room temperature, using cross-linking catalystswhich are biologically acceptable in the final polymer matrix and whichare compatible with the hormone components to be used in making thepolymer matrix dosage forms. Various suitable crosslinking agents can beused in crosslinking the above polymer, such as tetrapropoxy silane[Si(OCH₂ CH₂ CH₃)₄ ], if the silicone polymer has free hydroxy groupssuch as terminal hydroxy groups. A tin catalyst can be used for suchcrosslinking reaction. If a silicone polymer component has vinyl groups,it can be crosslinked with a dimethyl-silicone polymer using a catalystsuch as a platinum catalyst. Some suitable silicone polymers arecross-linkable copolymers having dimethyl and methylvinyl siloxaneunits, which can be cross-linked as by using a suitable peroxidecatalyst. Other cross-linking sites can be present in the polysiloxaneelastomers used. Suitable silicone medical-grade polymers are sold undethe designations Silastic 382, Q7-4635, Q7-4650, Q7-4665, Q7-4735,Q7-4750, Q7-4765 and MDX-4-4210.

The silicone polymers selected can also have a "block" or "graft"structure or both. By "block" structure is meant that the polymer canhave a section or block of the polymer chain structure of the polymerwhich can have a repeating unit of one type, such as dimethylsiloxane,and then have a succeeding block made up of repeating units of anothertype, such as methylvinylsiloxane, diphenylsiloxane, diisopropylsiloxane units or other siloxane or silane units or even of monomerunits of a compatible non siloxane or non-silane type. The blocks canvary in length and be repeated as desired. For example, if the blocksare represented as "A" and "B", respectively, the block copolymer can beA-B or A-B-A or A-B-A-B, etc. The "graft" structure simply means that tothe main polymer chain, one or more polymer chains are attached. Thosegrafted chains can have the same polymer units as those of the mainchain or can be different, as described above in connection with "block"copolymers. Also, the polymer used can be of a different type whereincopolymerizable monomers are placed together in a polymerization reactorso the main chain can have a certain population of each of the monomericunits.

The following are examples of block copolymers of the type which can beutilized in this invention. ##STR2## wherein y and z represent thenumber of repeating units sufficient to provide the desired property inthe polymer, such as from about 10 to about 5000.

Generally, those polymers used to form the biologically acceptablepolymer matrix are those capable of forming thin walls or coatingsthrough which hormones can pass at a controlled rate. Suitable polymersare biologically and pharmaceutically compatible, non-allergenic andinsoluble in and compatible with body fluids or tissues with which thedevice is contacted. The use of soluble polymers is to be avoided sincedissolution or erosion of the matrix would affect the release rate ofthe hormones as well as the capability of the dosage unit to remain inplace for convenience of removal.

Exemplary materials for fabricating the biologically acceptable polymermatrix include polyethylene, polypropylene, polyurethane,ethylene/propylene copolymers, ethylene/ethylacrylate copolymers,ethylene/vinyl acetate copolymers, silicone elastomers, especially themedical-grade polydimethylsiloxanes, neoprene rubber, polyisobutylene,polyacrylate, chlorinated polyethylene, polyvinyl chloride, vinylchloride-vinyl acetate copolymer, polymethacrylate polymer (hydrogel),polyvinylidene chloride, poly(ethylene terephthalate), butyl rubber,epichlorohydrin rubbers, ethylene-vinyl alcohol copolymer,ethylene-vinyloxyethanol copolymer; silicone copolymers, for example,polysiloxanepolycarbonate copolymers, polysiloxane-polyethylene oxidecopolymers, polysiloxane-polymethacrylate copolymers,polysiloxane-alkylene copolymers (e.g., polysiloxane-ethylenecopolymers), polysiloxane-alkylenesilane copolymers (e.g.,polysiloxane-ethylenesilane copolymers), and the like; cellulosepolymers, for example methyl or ethyl cellulose, hydroxypropyl methylcellulose, and cellulose esters; polycarbonates;polytetrafluoroethylene; and the like. For best results, thebiologically acceptable polymer matrix should be selected from polymerswith glass transition temperatures below room temperature. The polymermay, but need not necessarily, have a degree of crystallinity at roomtemperature. Cross-linking monomeric units or sites can be incorporatedinto such polymers. For example, cross-linking monomers can beincorporated into polyacrylate polymers, which provide sites forcross-linking the matrix after microdispersing the hormones into thepolymer. Known cross-linking monomers for polyacrylate polymers includepolymethacrylic esters of polyols such as butylene diacrylate anddimethacrylate, trimethylol propane trimethacrylate and the like. Othermonomers which provide such sites include allyl acrylate, allylmethacrylate, diallyl maleate and the like.

The adhesive means is suitably made in the form of a layer covering thehormone-containing disc and using a silicone adhesive, such as apolydimethylsiloxane adhesive depicted by the following formula:##STR3## wherein Me is methyl and R is Si(CH₃)₃.

For example, adhesive products or amine-resistant adhesive products soldby Dow Corning, such as the one sold under the designation DC-355, aresuitable for use in making the adhesive layer. The adhesive polymer mustbe biologically acceptable and compatible with the hormones and skinpermeation enhancer, if used. Certain polyacrylic adhesive polymers (inthe form of an alkyl ester, amide, free acid, or the like) orpolyisobutylene adhesive polymers can also be used with some hormones.Other suitable hypoallergenic pressure-sensitive contact adhesivecompositions can also be used. A preferred adhesive layer ispressure-sensitive.

However, depending upon economic and other factors, if desired, theadhesive means can be in the form of a ring attached, for example, to anextended portion of the backing layer so that the adhesive layer isadjacent to the sidewall of the hormone-containing disc layer. The widthof such adjacent adhesive ring must be adequate to hold the dosage unitsecurely to the subject being treated. Ordinarily, a suitable width ofsuch adhesive ring can be about 0.2 to about 1.2 cm, preferably about0.3 to about 1.0 cm.

The adhesive means then is finally covered in with a releasableprotective film layer which is made from materials which aresubstantially impermeable to the hormones, the skin permeation enhancer,if used, and any other components of the polymer matrix dosage unit. Thepolymer materials and metal foil laminates used for the backing layermay also be used to make the protective layer, provided the layer ismade strippable or releasable such as by applying conventionalsiliconizing. A suitable releasable material for use with siliconepolymer adhesive DC-355 is Scotchpak 1022 material sold by the 3MCompany.

In making the hormone-containing polymer matrix disc layer, siliconeelastomers such as polydimethylsiloxane of the formula described abovecan suitably be used. In making hormone-dispersed polymer matrix discdosage units, it has been found suitable to use a polyol such aspolyethylene glycol as a dispersing agent. Other suitable dispersingagents can also be used instead so long as they are effective.Water-soluble polyols are generally suitable. For example, polyethyleneglycols, such as those having a molecular weight of about 400, can beused, the molecular weight being variable therefrom, such as suitablybetween 300 and 1500. Other suitable dispersing agents known to theformulating art can be used. Depending upon the hormones and the drugloading desired, a suitable amount of a dispersing agent can be variedfrom zero to about 50 percent (by weight) based o the weight of thepolymer matrix disc. Commonly, the polyol is added as an aqueoussolution with the polyol content varying from 10 to about 50 percent,based on the volume of the final aqueous solution. Aqueous solutionshaving about 40 percent polyol ordinarily are suitable, with somevariation depending upon the rate of permeation desired, the particularhormones used, and at times, other factors. The hormones then are addedto the polymer used to make the matrix disc layer. The amount of thehormones added depends upon the amount of hormone dosage and theduration of treatment desired in each dosage unit and the amount whichcan be incorporated into the polymer matrix disc to retain suitablestructural, diffusion and other properties in the final matrix disc. Ithas been found, for example, that the hormones can be satisfactorilyadded to 70 parts of the polymer used in making the matrix disc, such assilicone elastomers. It has been found to be preferable to dissolve anddisperse the hormones used in an amount of a selected aqueous solutionof polyol, such as PEG 400. The mixture of the polymer and hormones orhormone-dispersing aqueous polyol solution is then thoroughly mixedusing a high-torque mixer to form a homogeneous microdispersion of thehormones in the polymer. With continued agitation, an amount ofcross-linking catalyst is desirably added together with a relatively lowmolecular weight polymer having a compatible chemical structure. Forexample, when polydimethylsiloxane based polymer is used as the polymer,a relatively low molecular weight polydimethylsiloxane and across-linking catalyst is added (such as 10 parts by weight of the lowmolecular weight polydimethylsiloxane and 30 drops of stannous octanoateper 100 g. amount of the final polydimethylsiloxane-hormone mixture) tothe above illustrative composition of 20 parts of hormone dispersion and70 parts or polydimethylsiloxane polymer. Again, the mixture is agitatedwith a high-torque mixer to form a uniform admixture. After each mixingstep, the composition is subjected to vacuum to remove entrapped air.

The deaereated mixture is then placed in a device maker and neated to asuitable elevated temperature to promote cross-linking. A suitabletemperature for cross-linking when the polymer used ispolydimethylsiloxane of the above formula and the cross-linking catalystis stannous octanoate, is from about 10° C. to about 200° C. desirablyabout 20° C. to about 100° C. The temperature used should not causesignificant degradation of the hormones. The polymer matrix sheetdesirably is about 0.05 to 5 mm, preferably about 0.1 to about 3 mm inthickness. The resulting cross-linked polymer matrix sheet is removedfrom the device maker and can be cut to form discs with desired shapesand sizes. The discs can be attached to a backing sheet, as preparedabove, using an adhesive. The disc alternatively can be made directly onthe backing sheet used. The discs generally should not exceed about 100sq. cm in area, suitably about 5 to 100 sq. cm, preferably, about 8 toabout 80 sq. cm, generally about 10 to 60 sq. cm being more preferable.The shape of the discs can vary; they can be circular, square,rectangular or other desired shape.

The hormone-containing polymer matrix disc layer, generally speaking,should contain some excess of the dispersed hormone over the dosageamount desired to be transdermally absorbed by the subject to betreated. Ordinarily, this excess is small, such as less than 2-foldexcess. Generally speaking, an amount of the hormone used, which issufficient, is less than 2 to about 10 times the desired dosage to aboutless than 2 to 5 times the desired dosage to be transdermally absorbedbeing adequate, depending upon the physiochemical properties of thehormones, as well as the nature of the polymer in the matrix disc layerand other factors.

The adhesive means, if it contains a skin permeation enhancer, is madeas by dissolving the enhancer compound in a solvent ior the enhancerwhich is compatible with the adhesive polymer solution used to make theadhesive layer containing the skin permeation enhancer. Any suitableamount ot solvent can be used as necessary to dissolve the quantity ofenhancer to be admixed with the adhesive polymer solution used. Forexample, 3 to 10 parts of solvent can be used to dissolve one part ofskin permeation enhancer, depending upon the solubility of the enhancer.When using polydimethylsiloxane adhesive solution, it has been foundsuitable to use 2 to 20 parts of skin permeation enhancer in 20 to 50parts of solvent (such as acetone, methyl ethyl ketone,trifluorotrichloroethane or other suitable solvent) and add the solutionto 100 parts of the adhesive solution. The enhancer - adhesivecombination is thoroughly mixed and a coating thereof is applied using afilm coating machine, directly onto the polymer matrix or to astrippable release liner before laminating onto the polymer matrix, asdescribed above. A suitable release liner is a poly(ethylene phthalate)laminated with aluminum foil or a Tefloncoated polyester film such assold under the designation Scotchpak 1022. The poly(ethylene phthalate)side to which the adhesive-enhancer coating is applied, is madestrippable by conventional siliconizing or by other suitable means. Thethickness of the adhesive enhancer layer normally is suitable about 10to about 200 microns, preferably about 30 to about 150 microns. Theamount of enhancer in the adhesive layer depends in part on the rapidityat which it is desired that the hormones be absorbed. Generallyspeaking, about 1 to about 30 percent of skin permeation enhancer basedon the weight of the adhesive is suitable, depending upon the enhancer,adhesive polymer, desired adhesiveness and other factors. Desirably,about 5 to about 20 percent of skin permeation enhancers are useddepending upon the above recited factors. The adhesive layer containingthe skin permeation enhancer is transferred to the polymer matrix discsurfaces by application of lamination technique under a constantpressure. Preferably, in order to assure adequate adhesion of theadhesive polymer layer to the skin of the subject treated, anenhancer-adhesive polymer solution having a relatively low concentrationof enhancer, e.g., 1-2 percent based on the weight of the adhesivepolymer is used to apply a coating to the release liner. The thicknessof this coating ordinarily is a minor percentage of the thickness of thefinal adhesive layer, such as 20-40 percent or the total adhesivepolymer layer. The remainder of the adhesive polymer layer having asuitable higher concentration oi the enhancer is used to coat the matrixdisc layer. Suitable higher concentrations of enhancer are usually 10 toabout 30 percent based on the adhesive polymer weight, the solubilityand desired final amount of skin enhancer agent and other factors. Thesolvent of the respective coatings is removed by evaporation. Therespective coatings are combined to make the final adhesivepolymer-enhancer agent layer by application of lamination techniqueunder a constant pressure.

The four-layer transdermal hormone polymer matrix dosage units areexcised. The backing layer, if desired, can be shaped around the sidesof the dosage unit, including the polymer matrix layer, if suchprotection is desired. The resulting hormone polymer matrix dosage unitforms are then placed in appropriate packaging for storage until theyare to be applied in transdermal treatment.

At least one estrogen and one progestin are dispersed in the polymermatrix disc layer. The specific hormones which may be dispersed in thepolymer matrix disc layer include any hormones which are capable ofbeing transdermally administered to a subject to be treated. With thecontrolled release of the hormone at a relatively steady rate over aprolonged period, typically several days and preferably one week, thesubject is provided with the benefit of a steady infusion of thefertility-controlling amounts of hormones over a prolonged period. Asexamples of hormones which can be included in the polymer matrix disclayer of the present invention, there may be mentioned the following:

It is presently preferred to use 17-beta-estradiol. It is a naturalhormone and ordinarily transdermally delivered by an adaptable system ofthis invention at a desirable daily rate while simultaneously apresently preferred progestin, the highly active levonorgestrel, isbeing transdermally absorbed at a desirably daily rate.17-beta-estradiol and levonorgestrel are compatible and can becodispersed in the matrix layer-forming polymer. The transdermal dosageunit designed for one-week therapy is required to deliver at least about20 mcg/20 cm² /day of levonorgestrel (or an equivalent effective amountof another progestin) and 20-50 mcg/20 cm² /day of 17-beta-estradiol (oran equivalent effective amount of another estrogen). That amount ofprogestin is believed to be necessary to inhibit ovulation and thatamount of estrogen is believed needed to maintain normal femalephysiology and characteristics. Derivatives of 17-beta-estradiol whichare biocompatible, capable of being absorbed transdermally andpreferably bioconvertible to 17-beta-estradiol beta-estradiol can alsobe used, if the amount of absorption meets the required daily dose ofthe estrogen component and if the hormone components are compatible.Such derivatives of estradiol include esters, either mono- or di-esters.The monoesters can be either 3- or 17- esters. The estradiol esters canbe, illustratively speaking, estradiol-3,17-diacetate;estradiol-3-acetate; estradiol-17-acetate; estradiol-3,17-divalerate;estradiol-3-valerate; estradiol-17-valerate; 3-mono, 17-mono and 3,17dipivilate esters; 3-mono, 17-mono and 3,17-dipropionate esters;corresponding cypionate, heptanoate, benzoate and the like esters;ethinyl estradiol; estrone; and other estrogenic steroids andderivatives thereof which are transdermally absorbable.

Combinations of the above or other with estradiol, for example, acombination of estradiol and estradiol-17-valerate or further acombination of estradiol-17-valerate and estradiol-3,17-divalerate canbe used with beneficial results. For example, 15-80% of each compoundbased on the total weight of the estrogenic steroid component can beused to obtain the desired result. Other combinations can also be usedto obtain desired absorption and levels of 17-beta-estradiol in the bodyof the subject being treated.

It will be appreciated that the hormones may be added to the abovemixture not only in the form of the pure chemical compound, but also inadmixture with other pharmaceuticals which may be transdermally appliedor with other ingredients which are not incompatible with the desiredobjective of transdermally administering the hormones to a patient.Thus, simple pharmacologically acceptable derivatives of the hormonessuch as ethers, esters, amides, acetals, salts and the like, ifappropriate, may be used. In some cases, such derivatives may actuallybe preferred.

The progestin hormone, as expressed above, is preferably levonorgestrel.Levonorgestrel is a potent progestin on a weight-dose basis, which is animportant factor since the progestins often show a lesser degree oftransdermal absorption than shown by 17-beta-estradiol and certainderivatives thereof. Other progestins which can be used in part or totalare norethindrone, norethynodrel and certain others. The progestin andestrogen hormones should have high compatibility with each other.

The progestin compound and the estrogenic steroid can ordinarily becompounded together in making the pharmaceutical dosage layer disc ofthis invention or can be microdispersed separately.

The skin permeation enhancers which can be used in carrying out thisinvention can vary. Ones that give preferred results with the polymermatrix dosage unit form having a specific hormone can vary. In someinstances, the use of permeation enhancer in making a polymer matrixdosage form will result in good or even excellent absorption for onehormone, may result in no or relatively low enhancement when anotherhormone is used. Use of combinations of two or more of the skinpermeation enhancer compounds frequently result in superior results,such as greater transdermal absorption.

Specific skin permeation enhancers which can be used in making thepolymer matrix dosage forms of this invention include saturated andunsaturated fatty acids and their esters, alcohols, monoglycerides,acetate, diethanolamides and N, N-dimethylamides, such as oleic acid,propyl oleate, oleyl acetate, propyl myristate, myristyl alcohol,myristyl N, N dimethyl amide, stearic acid and stearyl alcohol, stearylpropyl ester, monostearin, and combinations of them with, for example,1-dodecylazacycloheptan-2-one sold under the trademark Azone by NelsonResearch and Development; decyl methyl sulfoxide, dimethyl sulfoxide,salicylic acid and derivatives, N,N-diethyl-m-toluamide, crotamiton,1-substituted azacycloalkan-2-ones such as disclosed in U.S. Pat. No.4,316,893 (the 1-substituent having 0-17 carbon atoms, preferably, 1-11carbon atoms), and various other compounds which are biologicallycompatible and have transdermal permeation enhancement activity. Ethylalcohol and other short chain alkanols (with 1-4 carbon atoms) whichhave substantially the same properties and activity as ethyl alcohol donot come within the definition of skin permeation enhancer as usedherein.

The following examples are in illustration of the invention and are notintended to be limiting.

EXAMPLE 1

The following ingredients are used in making the hormone-containingpolymer matrix discs: 17-beta-estradiol, 1 part; levonorgestrel, 2.5parts; DC-360 polysiloxane medical fluid (20 cps), 12.4 parts; silicone(medical-grade) 382 elastomer (Silasti® 382 elastomer, Dow CorningCorporation), 74.1 parts; 10 parts of 40 percent (V/V) PEG 400/water(W/W); catalyst M, 20 drops per 100 g. of the mixture.

The 17-beta-estradiol and levonorgestrel are thoroughly mixed in the PEG400/water solution by using a high torque mixer (sold by Cole-ParmerCompany) at about 1000 RPM, to form a mixture of paste-like consistency.

The hormone mixture is added to silicone (medical-grade) 382 elastomerand mixed well, using the high-torque mixer, to form a homogeneoushormone (PEG) polymer dispersion. The DC-360 polysiloxane medical fluidis added using the high torque mixer to the hormone-polymer mixture and20 drops (for every 100 g of the mixture) of a cross-linking agent,which is designated as catalyst M and is stannous octanoate, are addedto the hormone-microdispersed elastomer mixture. After each addition,the material is thoroughly mixed, and the dispersed mixture is placedunder vacuum at 20 psi to remove entrapped air.

The hormone-polydimethylsil oxane dispersion is placed into a devicemaker and spread on a sheet of backing. A sheet of release liner isplaced over the spread out mixture The mixture is then cross-linked,using a pressure of 1000 psi at an elevated temperature (60° C.) for 30minutes to form a cross-linked, medicated polymer sheet, which has athickness of 0.2-3 mm.

The medicated polymer sheet is removed from the device maker and is cutinto square discs having rounded corners of about 10 sq. cm. The discsare attached to a backing layer of heat sealable polyester filmlaminated to aluminum foil, which is sold by 3M Company as Scotchpak1005 or 1006. The medicated discs are attached using an adhesive polymersolution, which is a silicone adhesive polymer sold by Dow Corning asDC-355.

The silicone adhesive is believed to have the following structure:##STR4##

The skin permeation enhancer-adhesive film is made as by using thefollowing ingredients: skin permeation enhancer, 6.5 parts; acetone 30parts; and adhesive polymer solution, 100 parts. The skin permeationenhancer-adhesive layer is made by dissolving the 6.5 parts by weight ofa skin permeation enhancer in 30 parts of acetone. The acetone solutionthen is added to 100 parts of a silicone adhesive solution sold byDow-Corning under the designation DC-355.

The mixture is thoroughly mixed to form a homogeneous mixture of skinpermeation enhancer and adhesive polymer, which is applied to a strip ofa release liner which is a siliconized, or a Teflon-coated polyesterfilm to permit easy removal of the release liner just prior toapplication of the final polymer matrix disc dosage unit to the subjectto be transdermally treated. The adhesive mixture is applied at acontrolled thickness. The formed layer has a thickness of about 50-200microns. The layer is dried completely in vacuum to remove volatilematter.

The skin permeation enhancer-adhesive polymer layer with release lineris applied onto the hormone-containing polymer matrix disc with theattached backing layer under a constant pressure to provide a firmlyadhered strip of a four-layered structure as follows:

1. Backing layer

2 Estradiol and levonorgestrel-containing polymer matrix layer

3. Skin permeation enhancer-adhesive layer

4. Release film layer which can be readily removed to permit applicationto the skin of the subject to receive transdermally the estradiol andlevonorgestrel.

By use of an appropriate cutter, the strip is cut to provide thetransdermal anti-fertility hormone polymer matrix dosage units which aresquare (with rounded corners) in shape and have an area of about 10 sq.cm.

The above polymer matrix disc dosage units can also be made to containstraight-chain saturated fatty acids (with alkyl chain length of C₄ toC₁₈), decyl methyl sulfoxide (DeMSO) or isopropyl myristate (IPM) orother skin permeation enhancers in the polymer matrix and/or in theadhesive layer.

The transdermal absorption of the hormones from the anti-fertilitypolymer matrix dosage units of this invention is evaluated by using askin specimen from a "hairless" mouse or human cadaver by following theprocedure described by P. R. Keshary and Y. W. Chien, in Drug Develop. &Ind. Pharm., 10 (6) 883-913 (1984).

Transdermal polymer matrix dosage units (MD Patches) are obtained andevaluated as shown in the following Tables and FIGS. 1-4.

    ______________________________________                                        Effect of Isopropyl Myristate in Adhesive Layer on Skin                       Permeation and Lag Time Profiles.sup.(1) of Estradiol from                    MDD Patches Containing Estradiol and Levonorgestrel.sup.(2)                                  Permeation Rate                                                               (mcg/cm.sup.2 /hr ±                                                                      Lag Time                                         Adhesive Composition.sup.(3)                                                                 S.D.)         (Hours ± S.D.)                                ______________________________________                                        (A)  No Adhesive   0.27 ± 0.048                                                                             14.5 ± 1.85                               (B)  Adhesive Only 0.26 ± 0.051                                                                             12.4 ± 1.10                               (C)  Adhesive with IPM:                                                            0.5 M         0.36 ± 0.054                                                                             19.8 ± 2.10                                    1.0 M         0.48 ± 0.066                                                                             22.0 ± 2.92                                    1.5 M         0.50 ± 0.069                                                                             18.9 ± 2.22                                    2.5 M         0.47 ± 0.050                                                                             20.6 ± 2.79                               ______________________________________                                         .sup.(1) 14 Samples were taken during 90 hours of study.                      .sup.(2) Fabricated from a formula which contains 5% (W/W) of                 levonorgestrel and 2.5% (W/W) of estradiol dispersed in separate              microreservoir compartment (10% W/W) containing aqueous 40% (V/V) PEG 400     solution.                                                                     .sup.(3) Enhancerincorporated adhesive coating layer is 16 microns thick.

    ______________________________________                                        Effect of Isopropyl Myristate in Adhesive Layer on Skin                       Permeation and Lag Time Profiles.sup.(1) of Levonorgestrel from               MDD Patches Containing Estradiol and Levonorgestrel.sup.(2).                                 Permeation Rate                                                               (mcg/cm.sup.2 /hr ±                                                                      Lag Time                                         Adhesive Composition.sup.(3)                                                                 S.D.)         (Hours ± S.D.)                                ______________________________________                                        (A)  No Adhesive   0.31 ± 0.049                                                                             32.5 ± 6.22                               (B)  Adhesive Only 0.16 ± 0.028                                                                             29.8 ± 3.45                               (C)  Adhesive with IPM:                                                            0.5 M         0.22 ± 0.037                                                                             28.9 ± 4.56                                    1.0 M         0.43 ± 0.076                                                                             36.6 ± 7.01                                    1.5 M         0.45 ± 0.072                                                                             33.2 ± 6.72                                    2.5 M         0.46 ± 0.066                                                                             32.8 ± 6.60                               ______________________________________                                         .sup.(1) 14 samples were taken during 90 hours of study.                      .sup.(2) Fabricated from a formula which contains 5% (W/W) of                 lovonorgestrel and 2.5% (W/W) of estradiol dispersed in separate              microreservoir compartment (10% W/W) containing aqueous 40% (V/V) PEG 400     solution.                                                                     .sup.(3) Enhancerincorporated adhesive coating layer is 16 microns thick.

    __________________________________________________________________________    Effect of Thickness of IPM-Containing Adhesive Coating on the Skin            Permeation Rate Profile.sup.(1)                                               of Estradiol from MDD Patches.sup.(2) Containing Estradiol and                Levonorgestrel                                                                               Permeation Rate Lag Time                                       Adhesive Composition                                                                         (mcg/cm.sup.2 /hr ± S.D.)                                                             % C.V.                                                                             (Hours ± S.D.)                                                                     % C.V.                                 __________________________________________________________________________    (A)                                                                              No Adhesive                                                                             .sup.a                                                                          0.31 ± 0.066                                                                          21.3 14.1 ± 2.94                                                                        20.9                                                .sup.b                                                                          0.28 ± 0.068                                                                          24.3 11.8 ± 2.80                                                                        23.7                                   (B)                                                                              Adhesive Only                                                                           .sup.a                                                                          0.31 ± 0.062                                                                          20.0 12.9 ± 2.70                                                                        20.9                                                .sup.b                                                                          0.29 ± 0.050                                                                          17.2 12.1 ± 2.02                                                                        16.7                                   (C)                                                                              Adhesive + IPM.sup.(3)                                                         12 microns                                                                             .sup.a                                                                          0.46 ± 0.071                                                                          15.4 15.9 ± 2.87                                                                        18.2                                                .sup.b                                                                          0.49 ± 0.089                                                                          18.2 16.8 ± 3.01                                                                        17.9                                       36 microns                                                                             .sup.a                                                                          0.52 ± 0.089                                                                          17.1 16.8 ± 3.11                                                                        18.5                                                .sup.b                                                                          0.56 ± 0.091                                                                          16.3 17.6 ± 2.77                                                                        15.7                                       60 microns                                                                             .sup.a                                                                          0.40 ± 0.071                                                                          17.8 14.9 ± 2.98                                                                        20.0                                                .sup.b                                                                          0.38 ± 0.066                                                                          17.5 15.2 ± 3.15                                                                        20.7                                      100 microns                                                                             .sup.a                                                                          0.42 ± 0.086                                                                          20.5 15.8 ± 2.12                                                                        13.4                                                .sup.b                                                                          0.38 ± 0.079                                                                          20.8 17.4 ± 3.02                                                                        17.4                                   __________________________________________________________________________     .sup.(1) 14 samples were taken during 103 hours of study.                     .sup.(2) Fabricated from a formula which contains 2.5% (W/W) of               levonorgestrel and 1.0% (W/W) of estradiol dispersed in microreservoir        (10% W/W) containing aqueous 40% (V/V) PEG solution.                          .sup.a Drugs were dispersed in separate microreservoirs.                      .sup.b Drugs were dispersed in the same microreservoir.                       .sup.(3) Each 12micron adhesive coating contains one molality of IPM.    

    __________________________________________________________________________    Effect of Thickness of IPM-Containing Adhesive Coating on the Skin            Permeation Rate Profile.sup.(1)                                               of Levonorgestrel from MDD Patches.sup.(2) Containing Estradiol and           Levonorgestrel                                                                               Permeation Rate Lag Time                                       Adhesive Composition                                                                         (mcg/cm.sup.2 /hr ± S.D.)                                                             % C.V.                                                                             (Hours ± S.D.)                                                                     % C.V.                                 __________________________________________________________________________    (A)                                                                              No Adhesive                                                                             .sup.a                                                                          0.30 ± 0.054                                                                          18.0 33.6 ± 4.2                                                                         12.5                                                .sup.b                                                                          0.28 ± 0.049                                                                          17.5 30.8 ± 4.9                                                                         15.9                                   (B)                                                                              Adhesive Only                                                                           .sup.a                                                                          0.18 ± 0.039                                                                          21.7 30.8 ± 5.4                                                                         17.5                                                .sup.b                                                                          0.20 ± 0.041                                                                          20.5 31.4 ± 5.8                                                                         18.5                                   (C)                                                                              Adhesive + IPM.sup.(3)                                                         12 microns                                                                             .sup.a                                                                          0.38 ± 0.061                                                                          16.1 35.4 ± 7.9                                                                         22.3                                                .sup.b                                                                          0.40 ± 0.079                                                                          19.8 36.2 ± 7.1                                                                         19.6                                       36 microns                                                                             .sup.a                                                                          0.43 ± 0.078                                                                          18.1 34.4 ± 7.0                                                                         20.3                                                .sup.b                                                                          0.45 ± 0.088                                                                          19.6 32.6 ± 5.9                                                                         18.1                                       60 microns                                                                             .sup.a                                                                          0.33 ± 0.054                                                                          16.4 30.8 ± 5.2                                                                         16.9                                                .sup.b                                                                          0.37 ± 0.068                                                                          18.4 31.6 ± 4.9                                                                         15.5                                      100 microns                                                                             .sup.a                                                                          0.39 ± 0.072                                                                          18.5 34.4 ± 7.1                                                                         20.6                                                .sup.b                                                                          0.38 ± 0.082                                                                          21.6 35.6 ± 6.9                                                                         19.4                                   __________________________________________________________________________     .sup.(1) 14 samples were taken during 103 hours of study.                     .sup.(2) Fabricated from a formula which contains 2.5% (W/W) of               levonorgestrel and 1.0% (W/W) of estradiol dispersed in microreservoir        (10% W/W) containing aqueous 40% (V/V) PEG solution.                          .sup.a Drugs were dispersed in separate microreservoirs.                      .sup.b Drugs were dispersed in the same microreservoir.                       .sup.(3) Each 12micron adhesive coating contains one molality of IPM.    

What is claimed is:
 1. A transdermal fertility-controlling polymermatrix dosage unit comprising:(a) a backing layer which is substantiallyimpervious to the fertility-controlling estrogen and progestin hormonesto be delivered transdermally; (b) a polymer matrix disc layer which isadhered to said backing layer and which has microdispersed thereineffective dosage amounts of fertility-controlling estrogen and progestinhormones said estrogen being selected from the group consisting of17-beta estradiol, ethinyl estradiol and biocompatible derivativesthereof convertible to said estradiols, progestin being selected fromthe group consisting of levonorgestrel and norethindrone, said polymerbeing bioacceptable and permitting said hormones to be transmitted fortransdermal absorption, said hormones being stable in said polymermatrix and being transdermally absorbed simultaneously to provide atleast minimum effective daily doses of said hormones to effect fertilitycontrol; and (c) an adhesive means for securing the dosage unit fortransdermal absorption to the subject treated.
 2. A transdermalfertility-controlling polymer matrix dosage unit of claim 1 wherein saidpolymer matrix layer has dispersed therein an effective amount of one ormore skin permeation enhancing agents.
 3. A transdermalfertility-controlling dosage unit of claim 1 wherein the polymer matrixis a silicone polymer or copolymer.
 4. A transdermalfertility-controlling polymer matrix dosage unit of claim 3 wherein thesilicone polymer or copolymer is a methyl silicone polymer or copolymeror a methylvinyl silicone polymer or copolymer.
 5. A. transdermalfertility-controlling polymer matrix dosage unit of claim 1 wherein thepolymer matrix disc layer is a crosslinked polysiloxane polymer of thefollowing formula: ##STR5## wherein R is selected from the groupconsisting of alkyl or alkoxy having 1-7 carbon atoms, vinyl, phenyl ora combination thereof; and wherein n is about 100 to about 5,000.
 6. Atransdermal fertility-controlling polymer matrix dosage unit of claim 3wherein the matrix is made up of microdispersed compartments having across-sectional dimension of from about 10 to about 200 microns.
 7. Atransdermal fertility-controlling polymer matrix dosage unit of claim 1wherein the estrogen hormone is 17-beta-estradiol.
 8. A transdermalfertility-controlling polymer matrix dosage unit of claim 1 wherein theprogestin is levonorgestrel.
 9. A transdermal fertility-controllingpolymer matrix dosage unit of claim 1 wherein the estrogen is17-beta-estradiol and the progestin is levonorgestrel.
 10. A transdermalfertility-controlling polymer matrix dosage unit of claim 1 wherein aneffective progestin dosage of at least about 20 mcg per day istransdermally delivered for at least for a term of more than one day toabout one week and an effective dose of estrogen of at least 20 istransdermally delivered for at least for a term of more than one day toabout one week.
 11. A transdermal fertility-controlling polymer matrixdosage unit of claim 10 wherein the progestin is levonorgestrel and theestrogen is 17beta-estradiol.
 12. A transdermal fertility-controllingpolymer matrix dosage unit of claim 6 wherein the progestin islevonorgestrel and the estrogen is 17-beta-estradiol.
 13. A transdermalfertility-controlling polymer matrix dosage unit of claim 1 wherein theprogestin is norethindrone and the estrogen is ethinyl estradiol.
 14. Atransdermal fertility-controlling polymer matrix dosage unit of claim 12wherein the silicone polymer is a cross-linked siloxane polymerlevonorgestrel is transdermally delivered at a dosage of at least about20 mcg per day for at least for a term of more than one day to about oneweek and 17-beta-estradiol is transdermally delivered at a dosage of atleast about 20 mcg per day for at least for a term of more than one dayto about one week, the microdispersed compartment having present aqueouspolyethylene glycol dispersing agent and the matrix layer having presentan enhancing amount of a skin permeation enhancing agent.
 15. Atransdermal fertility-controlling polymer matrix dosoage unit of claim12 wherein the silicone polymer is a cross-linked siloxane polymernorethindrone, is transdermally delivered at an effective dose for atleast for a term of more than one day to about one week and ethinylestradiol is transdermally delivered at an effective dialy dose for atleast for a term of more than one day to about one week, themicrodispersed compartment having present aqueous polyethylene glycoldispersing agent and the matrix layer having present an enhancing amountof a skin permeation enhancing agent.
 16. A transdermalfertility-controlling polymer matrix dosage unit of claim 13 wherein thedaily dose amounts are transdermally delivered for at least one week.17. A transdermal fertility-controlling polymer matrix dosage unit ofclaim 14 wherein the cross-linked silicone polymer ispolydimethylsiloxane.
 18. A transdermal fertility-controlling polymermatrix dosage unit of claim 4 wherein the cross-linked silicone polymeris a cross-linked methylvinyl silicone polymer.
 19. A transdermalfertility-controlling polymer matrix dosage unit of claim 5 wherein theskin permeation enhancing agent is present in the matrix layer, theadhesive layer or both layers and is selected from isopropyl myristate,straight chain fatty acids having an alkyl groups having 4 to 18 carbonatoms or decyl methyl sulfoxide.
 20. A transdermal fertility dosage unitof claim 16 wherein the skin permeation enhancing agent is present inthe matrix layer, the adhesive layer or both layers and is selected fromisopropyl myristate, straight chain fatty acids having an alkyl groupshaving 4 to 18 carbon atoms or decyl methyl sulfoxide.
 21. A process ofcontrolling fertility by applying to the skin of a subject desiring saidtreatment a dosage unit as described in claim 1 to provide at least theminimum effective dose amounts of progestin and estrogen for about thefirst three weeks of a menstrual cycle for successive menstrual cyclesfor a peroid extending as long as fertility control is desired.
 22. Aprocess of claim 19 wherein the dosage unit used is as described inclaim
 3. 23. A process of claim 19 wherein the dosage unit used is asdescribed in claim
 4. 24. A process of claim 19 wherein the dosage unitused is as described in claim
 6. 25. A process of claim 19 wherein thedosage unit used is as described in claim
 7. 26. A process of claim 19wherein the dosage unit used is as described in claim
 10. 27. A processof claim 19 wherein the dosage unit used is as described in claim 11.28. A process of claim 19 wherein the dosage unit used is as describedin claim
 12. 29. A process of claim 19 wherein the dosage unit used isas described in claim
 17. 30. A process of claim 19 wherein the dosageunit used is as described in claim 18.